The combination resulted in a 61% confirmed objective response rate in patients with the wild-type BRAF melanoma compared with 11% in those who received ipilimumab alone, reported F. Stephen Hodi, MD, of the Dana Farber Cancer Institute in Boston, and colleagues in the New England Journal of Medicine.

In patients with BRAF-mutant disease, the combination therapy had a 52% objective response rate, said Hodi, who presented the findings simultaneously at the American Association for Cancer Research annual meeting.

Ipilimumab is a monoclonal antibody that targets the CTLa-4 receptor, while nivolumab blocks the PD-1 protein on T cells.

"These results confirm the effectiveness of the two-drug combination," Hodi's group said. "It appears the drugs are boosting the immune system's response in a synergistic way, taking advantage of blocking two different brakes to the immune system."

Although a higher rate of toxicity was seen in the combination therapy group than in the monotherapy group, adverse events were manageable using standard safety guidelines, according to the investigators.

At present, ipilimumab alone is a standard first-line treatment for untreated patients with advanced melanoma if their tumors contain a normal or "wild type" version of the BRAF V600 gene. Nivolumab is approved for treatment following ipilimumab or a BRAF inhibitor for patients with a tumor that has a BRAF mutation.

"Targeted therapies, such as BRAF and MEK inhibitors that are approved for the treatment of patients with advanced melanoma who harbor BRAF V600 mutation-positive tumors, result in a high rate of initial tumor responses ...." the authors wrote. But the median duration of response is less than 1 year so there is a need for more treatment options, particularly in the 50% to 60% of patients with BRAF wild-type melanoma.

Study Details

The study enrolled 142 previously untreated patients with advanced melanoma (109 had the wild-type BRAF gene; 33 had BRAF mutations). They were randomly assigned in a 2:1 ratio to receive either ipilimumab (3 mg/kg) plus nivolumab (1 mg/kg) or placebo once every 3 weeks for four doses. This was followed by nivolumab (3 mg/kg) or placebo every 2 weeks until the occurrence of disease progression or unacceptable toxic effects.

Confirmed objective response among patients with BRAF V600 wild-type tumors as assessed by the investigators was the primary endpoint of the study.

A complete response (eradication of all visible signs of cancer) was observed in 16 of 72 patients (22%) who received combination therapy. There were no complete responses in either of the groups treated with ipilimumab plus placebo.

At the time of publication, the median response duration had not been reached with either of the drug regimens, the authors stated. And while median PFS had not been reached in the combination therapy group, it was 4.4 months in patients who received ipilimumab monotherapy for a hazard ratio 0.40 associated with combination therapy as compared with ipilimumab monotherapy for disease progression or death (95% CI 0.23-0.68, P<0.001).

In patients treated with the combination therapy, 54% had select grade 3 or 4 treatment-related adverse events, mainly colitis and diarrhea, within the first 15 weeks of treatment. In comparison, 24% of patients treated with ipilimumab alone reported serious adverse effects.

These adverse events typically took 9 weeks or less to resolve using immune-modulating medication. In most cases, immunosuppressive drugs effectively dampened the immune response and alleviated symptoms without affecting the anticancer benefits of the combination therapy.

"Aside from patients with endocrinopathies, which typically require continued hormone-replacement therapy, most patients had complete resolution of the serious adverse effects," Hodi stated. "Of those who discontinued treatment because of toxic effects, 68% had an objective response and most continue to have a response."

Of the 25 reported deaths in patients receiving combination therapy (27%) and 12 in the monotherapy group (37%), most were due to progressive disease, according to the investigators. Assessment determined that three deaths were related to the combination therapy and could be linked to pre-existing conditions or to medical procedures used to treat them. The investigators also concluded that none of the deaths in the monotherapy group were related to the study drug.

Study results also showed that there was no significant difference in response rates between patients whose pretreatment tumors were defined as PD-L1-positive versus those whose tumors were PD-L1-negative.

"These data suggest that PD-L1 should not be used to select patients to receive combination treatment," according to Hodi. The mechanism for response independent of baseline PD-L1 status remains unclear and requires further study, he added.

"The confirmed response rate associated with the combination therapy in this trial (61%) is higher than the 40% response rate that was recently reported with nivolumab monotherapy as first-line therapy in patients with advanced melanoma who have BRAF wild-type tumors," the authors noted, adding that the response rate with the combination therapy was "... higher than the rate observed in trials of monotherapy with pembrolizumab, another anti-PD-1 agent."

But they cautioned that patients in pembrolizumab trials had different demographic characteristics, making it difficult to compare the efficacy of the combination therapy with that of anti-PD-1 monotherapy.

It is anticipated that longer follow-up will produce a favorable clinical response, and that data from ongoing phase III double-blind randomized trials, such as the CheckMate 067 study, will further clarify the risk-benefit profile of combined PD-1 and CTLA-4 blockade versus monotherapy.

Case Study

In separate NEJM article, Paul B. Evans, MD and colleagues from Memorial Sloan Kettering Cancer Center in New York City, reported rapid eradication of a large tumor mass in a 49-year-old woman after a single treatment with the nivolumab-ipilimumab combination.

Evans and colleagues said they have now used this combination therapy in 13 patients with melanoma as part of an expanded-access program.

"We wish to bring this to the attention of our colleagues, not only as an example of the potential of immunotherapy to mediate dramatic and rapid antitumor effects, but also to point out a potential safety concern," they wrote.

The patient, who had melanoma and a history of persistent disease going back 4 years, presented with a large pedunculated necrotic mass under her left breast. A CT scan revealed left internal mammary lymphadenopathy, thought to be evidence of metastatic disease.

The patient underwent initial treatment with ipilimumab (3 mg/kg) and nivolumab (1 mg/kg). No substantial adverse effects were observed. When the patient returned 3 weeks later, the tumor had vanished leaving only a cavity where it had once been.

Treatment was delayed for one cycle because of a rash and scrapings from the cavity base were negative on cytologic examination. A repeat CT scan, performed 6 weeks after the initial treatment, revealed resolution of the chest wall mass and a decrease in the size of the left internal mammary lymphadenopathy.

Subsequently, the patient resumed treatment.

Evans and colleagues pointed out that this kind of antitumor effect, should it occur in common sites of metastatic melanoma such as the small bowel or myocardium, "could have grave consequences. It is ironic," they concluded, "that we are now concerned with the possibility of overly vigorous anti-melanoma responses."

The study by Hodi's group was supported by Bristol-Myers Squibb (BMS) and StemScientific.

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